Posted on by Dr. Francis Collins
Researchers continue to make progress with cancer immunotherapy, a type of treatment that harnesses the body’s own immune cells to attack cancer. But Kole Roybal wants to help move the field further ahead by engineering patients’ immune cells to detect an even broader range of cancers and then launch customized attacks against them.
With an eye toward developing the next generation of cell-based immunotherapies, this synthetic biologist at University of California, San Francisco, has already innovatively hacked into how certain cells communicate with each other. Now, he and his research team are using a 2018 NIH Director’s New Innovator Award to build upon that progress.
Roybal’s initial inspiration is CAR-T therapy, one of the most advanced immunotherapies to date. In CAR-T therapy, some of a cancer patient’s key immune cells, called T cells, are removed and engineered in a way that they begin to produce new surface proteins called chimeric antigen receptors (CARs). Those receptors allow the cells to recognize and attack cancer cells more effectively. After expanding the number of these engineered T cells in the lab, doctors infuse them back into patients to enhance their immune systems’s ability to seek-and-destroy their cancer.
As helpful as this approach has been for some people with leukemia, lymphoma, and certain other cancers, it has its limitations. For one, CAR-T therapy relies solely on a T cell’s natural activation program, which can be toxic to patients if the immune cells damage healthy tissues. In other patients, the response simply isn’t strong enough to eradicate a cancer.
Roybal realized that redirecting T cells to attack a broader range of cancers would take more than simply engineering the receptors to bind to cancer cells. It also would require sculpting novel immune cell responses once those receptors were triggered.
Roybal found a solution in a new class of lab-made receptors known as Synthetic Notch, or SynNotch, that he and his colleagues have been developing over the last several years [1, 2]. Notch protein receptors play an essential role in developmental pathways and cell-to-cell communication across a wide range of animal species. What Roybal and his colleagues found especially intriguing is the protein receptors’ mode of action is remarkably direct.
When a protein binds the Notch receptor, a portion of the receptor breaks off and heads for the cell nucleus, where it acts as a switch to turn on other genes. They realized that engineering a cancer patient’s immune cells with synthetic SynNotch receptors could offer extraordinary flexibility in customized sensing and response behaviors. What’s more, the receptors could be tailored to respond to a number of user-specified cues outside of a cell.
In his NIH-supported work, Roybal will devise various versions of SynNotch-engineered cells targeting solid tumors that have proven difficult to treat with current cell therapies. He reports that they are currently developing the tools to engineer cells to sense a broad spectrum of cancers, including melanoma, glioblastoma, and pancreatic cancer.
They’re also engineering cells equipped to respond to a tumor by producing a range of immune factors, including antibodies known to unleash the immune system against cancer. He says he’ll also work on adding engineered SynNotch molecules to other immune cell types, not just T cells.
Given the versatility of the approach, Roybal doesn’t plan to stop there. He’s also interested in regenerative medicine and in engineering therapeutic cells to treat autoimmune conditions. I’m looking forward to see just how far these and other next-gen cell therapies will take us.
 Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors. Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, Thomson M, Lim WA. Cell. 2016 Feb 11;164(4):780-91.
 Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors. Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, Walker WJ, McNally KA, Lim WA. Cell. 2016 Oct 6;167(2):419-432.e16.
Car-T Cells: Engineering Patients’ Immune Cells to Treat Cancers (National Cancer Institute/NIH)
Synthetic Biology for Technology Development (National Institute of Biomedical Imaging and Bioengineering/NIH)
Roybal Lab (University of California, San Francisco)
Roybal Project Information (NIH RePORTER)
NIH Support: Common Fund; National Cancer Institute
Posted on by Dr. Francis Collins
Inside our cells, strands of DNA wrap around spool-like histone proteins to form a DNA-histone complex called chromatin. Bradley Bernstein, a pathologist at Massachusetts General Hospital, Harvard University, and Broad Institute, has always been fascinated by this process. What interests him is the fact that an approximately 6-foot-long strand of DNA can be folded and packed into orderly chromatin structures inside a cell nucleus that’s just 0.0002 inch wide.
Bernstein’s fascination with DNA packaging led to the recent major discovery that, when chromatin misfolds in brain cells, it can activate a gene associated with the cancer glioma . This suggested a new cancer-causing mechanism that does not require specific DNA mutations. Now, with a 2016 NIH Director’s Pioneer Award, Bernstein is taking a closer look at how misfolded and unstable chromatin can drive tumor formation, and what that means for treating cancer.
Posted on by Dr. Francis Collins
Scientists have spent much time and energy mapping the many DNA misspellings that can transform healthy cells into cancerous ones. But recently it has become increasingly clear that changes to the DNA sequence itself are not the only culprits. Cancer can also be driven by epigenetic changes to DNA—modifications to chemical marks on the genome don’t alter the sequence of the DNA molecule, but act to influence gene activity. A prime example of this can been seen in glioblastoma, a rare and deadly form of brain cancer that strikes about 12,000 Americans each year.
In fact, an NIH-funded research team recently published in Nature Communications the most complete portrait to date of the epigenetic patterns characteristic of the glioblastoma genome . Among their findings were patterns associated with how long patients survived after the cancer was detected. While far more research is needed, the findings highlight the potential of epigenetic information to help doctors devise more precise ways of diagnosing, treating, and perhaps even preventing glioblastoma and many other forms of cancer.